Modern tomatoes have narrow genetic diversity limiting their improvement potential. We present a tomato pan-genome constructed using genome sequences of 725 phylogenetically and geographically ...representative accessions, revealing 4,873 genes absent from the reference genome. Presence/absence variation analyses reveal substantial gene loss and intense negative selection of genes and promoters during tomato domestication and improvement. Lost or negatively selected genes are enriched for important traits, especially disease resistance. We identify a rare allele in the TomLoxC promoter selected against during domestication. Quantitative trait locus mapping and analysis of transgenic plants reveal a role for TomLoxC in apocarotenoid production, which contributes to desirable tomato flavor. In orange-stage fruit, accessions harboring both the rare and common TomLoxC alleles (heterozygotes) have higher TomLoxC expression than those homozygous for either and are resurgent in modern tomatoes. The tomato pan-genome adds depth and completeness to the reference genome, and is useful for future biological discovery and breeding.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Branched actin networks are critical in many cellular processes, including cell motility and division. Arp2, a protein within the seven-membered Arp2/3 complex, is responsible for generating branched ...actin. Given its essential roles, Arp2 evolves under stringent sequence conservation throughout eukaryotic evolution. We unexpectedly discovered recurrent evolutionary diversification of Arp2 in Drosophila, yielding independently arising paralogs Arp2D in obscura species and Arp2D2 in montium species. Both paralogs are unusually testis-enriched in expression relative to Arp2. We investigated whether their sequence divergence from canonical Arp2 led to functional specialization by replacing Arp2 in D. melanogaster with either Arp2D or Arp2D2. Despite their divergence, we surprisingly found that both complement Arp2's essential function in somatic tissue, suggesting they have preserved the ability to polymerize branched actin even in a non-native species. However, we found that Arp2D- and Arp2D2-expressing males display defects throughout sperm development, with Arp2D resulting in more pronounced deficiencies and subfertility, suggesting the Arp2 paralogs are cross-species incompatible in the testis. We focused on Arp2D and pinpointed two highly diverged structural regions-the D-loop and C terminus-and found that they contribute to germline defects in D. melanogaster sperm development. However, while the Arp2D C terminus is suboptimal in the D. melanogaster testis, it is essential for Arp2D somatic function. Testis cytology of the paralogs' native species revealed striking differences in germline actin structures, indicating unique cytoskeletal requirements. Our findings suggest canonical Arp2 function differs between somatic versus germline contexts, and Arp2 paralogs may have recurrently evolved for species-specialized actin branching in the testis.
Pre-existing comorbidities such as obesity or metabolic diseases can adversely affect the clinical outcome of COVID-19. Chronic metabolic disorders are globally on the rise and often a consequence of ...an unhealthy diet, referred to as a Western Diet. For the first time in the Syrian hamster model, we demonstrate the detrimental impact of a continuous high-fat high-sugar diet on COVID-19 outcome. We observed increased weight loss and lung pathology, such as exudate, vasculitis, hemorrhage, fibrin, and edema, delayed viral clearance and functional lung recovery, and prolonged viral shedding. This was accompanied by an altered, but not significantly different, systemic IL-10 and IL-6 profile, as well as a dysregulated serum lipid response dominated by polyunsaturated fatty acid-containing phosphatidylethanolamine, partially recapitulating cytokine and lipid responses associated with severe human COVID-19. Our data support the hamster model for testing restrictive or targeted diets and immunomodulatory therapies to mediate the adverse effects of metabolic disease on COVID-19.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Noncanonical inflammasome activation by cytosolic lipopolysaccharide (LPS) is a critical component of the host response to Gram-negative bacteria. Cytosolic LPS recognition in macrophages is preceded ...by a Toll-like receptor (TLR) priming signal required to induce transcription of inflammasome components and facilitate the metabolic reprograming that fuels the inflammatory response. Using a genome-scale arrayed siRNA screen to find inflammasome regulators in mouse macrophages, we identified the mitochondrial enzyme nucleoside diphosphate kinase D (NDPK-D) as a regulator of both noncanonical and canonical inflammasomes. NDPK-D was required for both mitochondrial DNA synthesis and cardiolipin exposure on the mitochondrial surface in response to inflammasome priming signals mediated by TLRs, and macrophages deficient in NDPK-D had multiple defects in LPS-induced inflammasome activation. In addition, NDPK-D was required for the recruitment of TNF receptor-associated factor 6 (TRAF6) to mitochondria, which was critical for reactive oxygen species (ROS) production and the metabolic reprogramming that supported the TLR-induced gene program. NDPK-D knockout mice were protected from LPS-induced shock, consistent with decreased ROS production and attenuated glycolytic commitment during priming. Our findings suggest that, in response to microbial challenge, NDPK-D-dependent TRAF6 mitochondrial recruitment triggers an energetic fitness checkpoint required to engage and maintain the transcriptional program necessary for inflammasome activation.
We remain largely without effective prophylactic/therapeutic interventions for COVID-19. Although many human COVID-19 clinical trials are ongoing, there remains a deficiency of supportive preclinical ...drug efficacy studies to help guide decisions. Here we assessed the prophylactic/therapeutic efficacy of hydroxychloroquine (HCQ), a drug of interest for COVID-19 management, in 2 animal disease models. The standard human malaria HCQ prophylaxis (6.5 mg/kg given weekly) and treatment (6.5 mg/kg given daily) did not significantly benefit clinical outcome, nor did it reduce SARS-CoV-2 replication/shedding in the upper and lower respiratory tract in the rhesus macaque disease model. Similarly, when used for prophylaxis or treatment, neither the standard human malaria dose (6.5 mg/kg) nor a high dose (50 mg/kg) of HCQ had any beneficial effect on clinical disease or SARS-CoV-2 kinetics (replication/shedding) in the Syrian hamster disease model. Results from these 2 preclinical animal models may prove helpful in guiding clinical use of HCQ for prophylaxis/treatment of COVID-19.
Abstract
Francisella tularensis subsp. tularensis (Ftt) is a highly pathogenic, intracellular bacterium capable of replicating while avoiding detection by the host immune system. An O-antigen ...polysaccharide capsule has been identified as an important virulence factor involved in suppressing the immune response. Previous studies have shown that Ftt capsule limits the metabolic shift from oxidative phosphorylation to glycolysis needed for activation of host defense mechanisms. The specific mechanism by which Ftt capsule alters host metabolism is not fully understood but involves improvement of mitochondrial function. In this study, central metabolism in primary cell culture was mapped using targeted metabolomics following TLR stimulation and capsule treatment. Consistent with previous findings, capsule stimulated TCA cycle activity to increase mitochondrial respiration. Ftt capsule treatment did not inhibit increased glycolytic flux associated with TLR-induced metabolic activation. However, capsule limited accumulation of lactate and depletion of acetyl-CoA pools associated with TLR-driven uncoupling of glycolysis and the TCA cycle. These data point to capsule-dependent manipulation of pyruvate dehydrogenase, the enzyme responsible for converting pyruvate made during glycolysis into acetyl-CoA for utilization within the TCA-cycle. Together, these results demonstrate a novel mechanism by which a bacterial capsule can limit inflammation by maintaining coupling of central metabolic pathways.
The Digital Public Domain Dulong de Rosnay, Melanie; Martin, Juan Carlos De; Abelson, Hal ...
2012
Book
Open access
Digital technology has made culture more accessible than ever before. Texts, audio, pictures and video can easily be produced, disseminated, used remixed using devices that are increasingly ...user-friendly and affordable. However, along with this technological democratization comes a paradoxical flipside: the norms regulating culture's use — copyright and related rights — have become increasingly restrictive. This book brings together essays by academics, librarians, entrepreneurs, activists and policy maders, who were all part of the EU-funded Communia projetc. Together the authors argue that literature, music, the output of scientific research, educational material or public sector information — is fundamental to a healthy society. The essays range from more theoretical papers on copyright and the history of the public domain, to practical examples and case studies of recent projects that have engaged with the principles of Open Access and Creative Commons licensing. The Digital Public Domain opens up discussion and offers practical solutions to the difficult question of the regulation of culture in the digital age.
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